Bacteria are very adaptable microorganisms that possess the ability to adapt and to survive under adverse conditions. Doctors in hospitals and clinics around the world are losing the battle against an onslaught of new drug resistant bacterial infections including those caused by Staphylococci, Streptococci, Enterococci and Pseudomonas.
Bacterial resistance to the current antibiotics has been on a steep rise due to the alteration of the target, a change in the permeability pattern or by efflux of active ingredient and by deactivation of the antibiotic before reaching the active site.
The β-lactam antibiotics (penicillins, cephalosporins, monobactams and carbapenems) are the most widely used group of antibiotics for the treatment of many infectious diseases, because of proven clinical efficacy and their excellent safety profile. Bacterial resistance towards gram-positive pathogens against β-lactam antibiotics is mainly due to the alteration of penicillin binding proteins (PBP's), efflux of active ingredient and deactivation of active ingredient. Whereas bacterial resistance towards gram-negative pathogens against β-lactam antibiotics in addition to those of the gram-positive pathogen, also are due to changes in outer membrane permeability pattern.
To overcome the changes in outer membrane permeability, in recent years a number of β-lactam compounds (cephem and monobactam) containing an iron chelating catecholic and dihydroxypyridone groups have been reported (29Th ICAAC, Houston Tex., Sep. 18, 1989, abstract no. 355, 356; 30th ICAAC, Atlanta, Ga., Oct. 22, 1990, abstract no. 458; Antimicrobial Agents and chemotherapy 1991, 35, 104-110). The potent activity of these compounds is due to their utilization of the TonB-dependent iron transport systems for transport across the bacterial outer membrane (Antimicrobial Agents and chemotherapy 1995, 39, 613-619).
Monobactams are a class of antibacterial agents and have been used to treat infections caused by gram-negative microorganisms. Currently Aztreonam and Carumonam are in clinical use. Quinoxaline directly attached to an oxime side chain of the monobactam nucleus is under development (Curr. Opin. Anti-infect. Drugs 1999, 1(1), 96-100; Antimicrobial Agents and Chemotherapy 1997, 41, 1010-1016). Further dihydroxypyridine through a methylene spacer attached to an oxime side chain in the anti orientiation is reported as β-lactamase inhibitor (U.S. Pat. No. 5,888,998 (1999)).
The present invention describes a class of compound in which a dihydroxypyridone group is directly or through a suitable spacer attached to an oxime side chain in a monobactam nucleus and its use to treat gram-negative infections, particularly those caused by Pseudomonas. Pseudomonas aeruginosa continues to be a very frequent opportunistic pathogen, capable of causing a wide variety of infections in the immunocompromised patient. These infections are often associated with significant morbidity and are difficult to treat.